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My mother was murdered by what I call corporate and political homicide i.e. FOR PROFIT! she died from a rare phenotype of CJD i.e. the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. sporadic, simply meaning from unknown route and source. I have simply been trying to validate her death DOD 12/14/97 with the truth. There is a route, and there is a source. There are many here in the USA. WE must make CJD and all human TSE, of all age groups 'reportable' Nationally and Internationally, with a written CJD questionnaire asking real questions pertaining to route and source of this agent. Friendly fire has the potential to play a huge role in the continued transmission of this agent via the medical, dental, and surgical arena. We must not flounder any longer. ...TSS

This report presents the results of our audit concerning FSIS management of the national residue program, especially as it relates to cattle. Your response to the official draft report, dated March 2, 2010, is included at the end of the report. Excerpts of the response, along with Office of Inspector General’s position, are incorporated into the Findings and Recommendations section of the report. Based on your responses, we were able to reach management decision on all of the report’s 14 recommendations. Please follow your agency’s internal procedures in forwarding documentation for final action to the Office of the Chief Financial Officer.

We appreciate the courtesies and cooperation extended to us by members of your staff during this audit.

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FSIS National Residue Program for Cattle

Executive Summary

One of the public food safety issues facing the United States is the contamination of meat with residual veterinary drugs, pesticides, and heavy metals. “Residue” of this sort finds its way into the food supply when producers bring animals to slaughter plants while they have these residual contaminants in their system. When the animals are slaughtered, traces of the drugs or pesticides contained in these animals’ meat is shipped to meat processors and retail supermarkets, and eventually purchased by consumers. In order to safeguard the Nation’s food supply from harmful residue, the U.S. Department of Agriculture’s (USDA) Food Safety and Inspection Service (FSIS) administers the national residue program. FSIS inspectors sample meat processed through slaughter plants for residue testing and compare the results with tolerances established by the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) to prevent adulterated meat from entering into commerce.2 The Office of Inspector General (OIG) initiated this audit to evaluate the effectiveness of the national residue program and to assess how well FSIS, FDA, and EPA were coordinating to accomplish the program’s objectives.

Based on our review, we found that the national residue program is not accomplishing its mission of monitoring the food supply for harmful residues. Together, FSIS, FDA, and EPA have not established thresholds for many dangerous substances (e.g., copper or dioxin3), which has resulted in meat with these substances being distributed in commerce. Additionally, FSIS does not attempt to recall meat, even when its tests have confirmed the excessive presence of veterinary drugs.

To address these serious shortcomings in the national residue program, FSIS, EPA, and FDA need to take steps to improve how they coordinate with one another to accomplish the program’s mission. Recognizing that they needed to work together to prevent residue from entering the food supply, the three agencies established the Surveillance Advisory Team (SAT) and the Interagency Residue Control Group (IRCG) as a way of coming together to communicate and coordinate.4 We found, however, that there were a wide range of problems with relying on this process: not all agencies were equally committed to the SAT and IRCG; essential participants were not required to attend; and no one agency had authority to ensure that necessary actions were taken to deal with disagreements. Due to problems with how the SAT and IRCG were established and were functioning, we identified four issues relating to coordination between FSIS, EPA, and FDA. The three agencies involved need to: 1) expand the substances they test

1 Pesticides are any substance intended for preventing, destroying, repelling, or mitigating any pest (e.g., insects or mice) or any substance intended for use as a plant regulator, defoliant, or desiccant. 2 When violative levels of residues are detected in food-producing animals submitted for slaughter, the product found to be contaminated with violative residues is considered “adulterated” and is subject to condemnation and disposal. If the product has already been released into commerce, then FSIS evaluates the hazard the product poses to the public and, based on this analysis, determines whether to request a product recall by the firm that manufactured the adulterated product. 3 Dioxins are formed as a result of combustion processes, such as waste incineration and the burning of fuels (e.g., wood, coal, or oil). Exposure to large amounts of dioxins may cause skin diseases, mild liver damage, cancer, reproductive problems, or developmental effects. 4 The SAT meets annually with the primary function of establishing the sampling plan for the national residue program’s scheduled sampling for the next year. The IRCG meets monthly to address ongoing issues concerning the national residue program.

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for, 2) improve their methodology for sampling hazardous residues, 3) determine more efficient ways of approving newer methods of testing for drug residues, and 4) collaborate to set tolerances for additional residues.

FSIS, EPA, and FDA Need to Expand the Substances They Test For

Each year, the SAT brings together representatives from FSIS, EPA, and FDA to decide which residues they will include in the approximately 120 substances they test for annually. Although EPA routinely asks FSIS to test for pesticides that the three agencies have together determined to be high health risks, FSIS has, for many years, continued to test for only one type of pesticide, citing its limited resources and the fact that EPA has not established tolerances for

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2

many varieties of pesticides.

We acknowledge that FSIS’ laboratory testing resources are not unlimited and that the agency must make decisions about what it will and will not test for. However, if EPA, FDA, and FSIS determine that there are additional high risk substances that should be tested, the SAT needs a mechanism for resolving differences and, if necessary, obtaining necessary testing resources. One such mechanism would be to elevate such disagreements to executive-level officials capable of arriving at an appropriate compromise. A 1984 memorandum of understanding to coordinate Federal residue monitoring activities was signed by the FSIS Administrator and other officials at FDA and EPA below the Administrator’s level. We believe that residue monitoring is of such importance that the framework of the program should be re-established and approved at the highest levels within the respective Departments.

FSIS, FDA, and EPA Need to Improve Their Methodology for Sampling Hazardous Residues

Once the three agencies involved have determined which substances they will test for, they then decide how they will sample for those substances. We found, however, that different groups have questioned FSIS’ sampling methodology, both its sample size and design. For example, FSIS laboratory personnel believe that they should be testing more than 300 samples for some residues, while an outside contractor performing a quality control review recommended that FSIS could test fewer samples “without a significant loss in precision.” Members of the SAT and IRCG have also proposed that sampling for some veterinary drugs quarterly instead of monthly would provide equally useful information and could also save laboratory resources.

The SAT is the appropriate forum for discussing issues concerning FSIS’ sample design, but at present, the appropriate agency managers and personnel with the relevant qualifications do not always attend SAT meetings, and the agencies have not conducted a thorough review of how they design the sample for these substances. The three agencies should work together to strike a balance between sampling demands, resource limitations, and the relative importance of any given compound. Following appropriate risk analysis principles would provide FSIS with a scientific and structured approach that would also allow the agency to optimize its limited laboratory resources. FSIS and FDA Need to Determine More Efficient Ways of Approving Newer Methods of Testing for Drug Residues

When testing for the various types of drug residue that the agencies have determined to be high risk, FSIS relies on FDA to approve the testing methods it uses. However, the approved methods are often antiquated and ineffective because they were approved when FDA first approved the drug. “Bridging” testing methods—confirming that a newer and more efficient method will yield acceptable results when compared to the FDA-approved method—is a slow and difficult process, and FDA is not always willing, or able, to undertake the work.

Although FDA and FSIS disagree on how to solve this problem, they agree that until the problem is resolved, FSIS will not be able to test for residues as efficiently as possible. FSIS and FDA should cooperate to improve their efficiency in approving newer methods for FSIS to use in testing for residues, as doing so will enable FSIS to take advantage of advanced technologies, lower its costs, and improve the quality of its analyses.

FSIS, EPA, and FDA Need to Collaborate to Set Tolerances for Additional Residues

If FSIS confirms the presence of residue in a sample of meat, it needs a “tolerance” or a threshold for determining if the concentration of that residue is dangerous for human consumption. For example, FDA has set a tolerance of .05 parts per million for penicillin in beef, so FSIS knows that beef with 10.62 parts per million should be excluded from the food supply. FSIS relies on FDA or EPA to set tolerances for drugs, pesticides, and heavy metals.

We found, however, that tolerances have not been set for many potentially harmful substances, which can impair FSIS’ enforcement activities. For example, in 2008, when Mexican authorities rejected a shipment of U.S. beef because it contained copper in excess of Mexico’s tolerances, FSIS had no basis to stop distribution of this meat in the United States since FDA has set no tolerance for copper. Though we acknowledge that setting tolerances is an expensive and time-consuming process, FSIS needs a systematic and formal process to request FDA and EPA to set tolerances for residues that are deemed potentially hazardous. FSIS also needs procedures that specify what actions agency personnel are to take regarding the disposition of carcasses that contain potentially hazardous substances when there are no formal tolerances established by EPA or FDA.

Along with the issues of coordination among the three agencies involved in the national residue program, we found that FSIS itself can take action to strengthen the program by requiring slaughter plants to increase their controls when processing dairy cows and bob veal.

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5 Plants handling dairy cows and bob veal were, in 2008, responsible for over 90 percent of residue violations found. FSIS allowed such plants to continue treating residue problems as “not reasonably likely to occur”—the determination that would allow plants to justify not implementing additional procedures to control residues. Although FSIS had reviewed these plants’ control plans multiple times, agency officials explained that they had not done the analysis to determine that violations were so concentrated among dairy cows and bob veal. As a result, in 2008, individual plants amassed as many as 211 violations—with 21 producers having

5

Bob veal are calves, usually unwanted male calves born at dairy operations, that are slaughtered within a few days of birth.

multiple violations—and still were able to treat residue as a problem “not reasonably likely to occur.” FSIS has had a longstanding problem of not being able to identify the producers of cattle that have tested positive for residue, as dairy cows often pass through several buyers and sellers before they are presented for slaughter by suppliers. Without this information, FSIS will always be limited in its ability to respond to repeat violators and to prevent such cattle from entering the slaughter plants. In order to resolve this problem, it would be in FSIS’ interest to require that plants with a history of residue violations identify the producers of any animals presented for slaughter, so that plants can take proactive measures to prevent or control shipments of cattle at high risk for residues and FSIS can subject the animals to additional testing.

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6 However, FSIS officials explained that the Agency does not have the authority to require plants to obtain producer identification for animals arriving for slaughter.7 As an alternative to obtaining the authority to request producer identification, FSIS should establish procedures that provide incentives for the plants with a history of residue violations to voluntarily request producer’s identification for any animal presented for slaughter, such as subjecting every shipment of cattle from unknown producers to additional on-site screening for potential residue testing. Additionally, since FSIS already maintains repeat violator information, it should establish performance measures, such as tracking reductions in the occurrence of repeat residue violations over time.

We also found that FSIS does not recall meat adulterated with harmful residue, even when it is aware that the meat has failed its laboratory tests. Between July 12, 2007, and March 11, 2008, FSIS found that four carcasses were adulterated with violative levels of veterinary drugs8 and that the plants involved had released the meat into the food supply. Although the drugs involved could result in stomach, nerve, or skin problems for consumers, FSIS requested no recall. Officials explained that when meat enters commerce, the agency must prove that consuming a single serving of the contaminated meat is likely to cause harm. In these cases, FSIS determined that consumers would not likely be “acutely harmed” by consuming a single serving of this meat so it could be difficult to force a plant to implement a voluntary recall. In addition, FSIS faces the task of convincing a U.S. Attorney to file for the product seizure in federal district court if the plant refuses the voluntary recall. According to FSIS officials, seizure of the product is not likely for non-acute health risks, e.g., a small amount of residue adulterated product from a single carcass. However, in the past, FSIS has requested plants initiate voluntary Class II recalls for “low” risk health situations for non-acute causes, such as distribution of product that was produced from animals that had not received a proper ante-mortem inspection.

Finally, we found that FSIS needs to modernize its process for sampling carcasses at slaughter plants and then testing those samples at its laboratories so that the agency can make use of readily available technologies, including barcode scanning, electronic forms for retaining information, and an electronic reservation system for scheduling tests. At present, the agency

6

This additional testing was recently required by FSIS publication of Notice 04-09, in January, 2009.

7

FSIS does have the authority to require producer identification for producers bringing bob veal into slaughter under 9 Code of Federal Regulations 309.16(d)(2), which states that “[t]he identity of the producer of each calf presented for ante-mortem inspection shall be made available by the official establishment to the inspection [inspector] prior to the animal being presented for ante-mortem inspection.”

8

These drugs were Ivermectin, Sulfadimethoxine, Florfenicol, and Sulfamethazine, which are anti-parasitic or anti-bacterial agents.

relies on a system that requires employees to make pen and paper notes on tags that are affixed to carcasses—a system that is slow, cumbersome, and not always very legible. FSIS officials stated that they did not realize their technology was out-of-date and did not know that some plants were already using newer and more innovative techniques for tracking carcasses. Due to this problem, FSIS’ public health veterinarians had less time to devote to their primary mission of inspecting and testing animal carcasses for harmful adulterants, and FSIS was testing meat samples for residue less efficiently and reliably than was necessary. We concluded that FSIS—both alone and in collaboration with FDA and EPA—needs to take a number of important steps to strengthen the national residue program. Those steps should ensure that the program is effectively accomplishing its objectives of ensuring that adulterated meat is not entering the U.S. food supply.

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Background & Objectives

Background

As the public health agency of USDA, FSIS administers the national residue program to ensure that the Nation’s food supply is safe from the residues of veterinary drugs, pesticides, and heavy metals that might find their way into meat destined for human consumption.

The effects of these residues on human beings who consume such meat are a growing concern. Not only does overuse of antibiotics help create antibiotic-resistant strains of diseases, but the residues of certain drugs and heavy metals can have potentially adverse health consequences if they are consumed in meat. The following table shows five drugs or substances and the potential side effects or health consequences:

Ivermectin Neurotoxicity (e.g., altering normal activity of the nervous system which can eventually disrupt or even kill neurons, key cells that transmit and process signals from the brain).

Residues of drugs, pesticides, and heavy metals differ from microbiological pathogens like E. coli,11 Salmonella, and Listeria Monocytogenes, which the public more readily associates with food safety. While cooking meat properly can destroy these pathogens before they are consumed, no amount of cooking will destroy residues. In some cases, heat may actually break residues down into components that are more harmful to consumers. Since consumers have no easy way of protecting themselves against the residues of harmful substances in their food, it is important that the national residue program’s controls be as robust as possible to prevent meat contaminated with harmful substances from reaching the kitchen table.

11

For purposes of this report, we refer to Escherichia coli O157:H7 simply as E. coli.

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Section 2: FSIS Needs to Strengthen Oversight at Plants and Upgrade the National Residue Program’s Technology

FSIS has not required that slaughter plants processing dairy cows and bob veal implement adequate controls to ensure that residue is not entering the food supply, even though these plants are at much higher risk than plants processing beef cattle. This has occurred because Hazard Analysis and Critical Control Point (HACCP) principles allow slaughter plants themselves to make the determination as to whether residue problems were “reasonably likely to occur”—the threshold for implementing additional controls—and the primary function of the FSIS plant-level personnel is not to challenge the hazardous risk assessment but to verify or monitor the plant’s application of the existing controls. FSIS did not exercise additional oversight despite the fact that plants handling dairy cows and bob veal were responsible for over 90 percent of residue violations in 2008.

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33 Agency officials had not performed the analysis necessary to determine that violations were concentrated within dairy cows and bob veal, and they regard residue as a lower priority than other sorts of adulterants, such as E. coli and Salmonella. As a result, in 2008, one plant amassed as many as 211 violations—another had 21 producers with multiple violations—and other plants treated residue as a problem “not reasonably likely to occur” (see Table 1, below). Furthermore, we verified that at least four beef carcasses were adulterated with violative levels of residue, entered commerce, and were not recalled by the slaughter plant or FSIS.34

The following table summarizes the number of residue violations at 7 selected cattle slaughter establishments during the 2008 calendar year. The violation data was taken from the Residue Violation Information System (RVIS).35 This information includes OIG’s assigned plant identification number (1 – 7), the number of residue violations at each plant, the number of repeat offenders that delivered cattle to the plant, the number of residue violations that occurred at the plant from repeat offenders, and the overall percentage of residue violations at the plant that came from repeat offenders.

33

The 2008 data from the RVIS database was the most recent full calendar year information available at the time of our field work.

34

Since FSIS did not request a voluntary recall by the establishments, the plants did not collect the production data necessary for FSIS to determine the number of pounds of product from the four carcasses with the violative amounts of Ivermectin, Sulfadimethoxine, Florfenicol, and Sulfamethazine.

35

During the course of our audit, we did not verify information in the RVIS, and make no representation of the adequacy of the system or the information generated from it.

On October 6, 7, 8, 13, and 14, 2009, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 1008 Grinstead Mill Road, Cave City, Kentucky 42127-9601. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about July 6, 2009, you sold a culled dairy cow, identified with back tag (b)(4) for slaughter as food. On or about July 7, 2009, (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of 35.936 parts per million (ppm) of sulfamethazine residue in the muscle tissue and the presence of 32.294 ppm of sulfamethazine residue in the liver tissue. FDA has established a tolerance of 0.1 ppm for residues of sulfamethazine in the uncooked edible tissues of cattle as codified in Title 21, Code of Federal Regulations (C.F.R.), 556.670 (21 C.F.R. 556.670). The presence of this drug in edible tissue from this animal in this amount causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain treatment records. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4).

We also found that you adulterated the new animal drug sulfamethazine. Specifically, our investigation revealed that you did not use sulfamethazine as directed by its approved labeling. Use of this drug in this manner is an extra-label use. See 21 C.F.R. 530.3(a). In addition, the extra-label use of sulfamethazine is prohibited in lactating dairy cows under 21 C.F.R. 530.41(a)(9).

The extra-label use of approved new animal or human drugs in animals is allowed under the Act only if the extra-label use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Our investigation found that you administered sulfamethazine to the culled dairy cow identified with back tag (b)(4) without following the dose and withdrawal period as stated in the approved labeling. Sulfamethazine is prohibited for extra-label use in lactating dairy cows by 21 C.F.R. 530.41(a)(9). Furthermore, your extra-label use of sulfamethazine resulted in an illegal drug residue, in violation of 21 C.F.R. 530.11(d). Because your use of this drug was not in conformance with its approved labeling and did not comply with 21 C.F.R. Part 530, you caused the drug to be unsafe under section 512(a) of the Act, 21 U.S.C. 360b(a), and adulterated within the meaning of section 501(a)(5) of the Act, 21 U.S.C. 351(a)(5).

The above is not intended to be an all-inclusive list of violations. As a producer of animals offered for use as food, you are responsible for ensuring that your overall operation and the food you distribute is in compliance with the law.

You should take prompt action to correct the violations described in this letter and to establish procedures to ensure that these violations do not recur. Failure to do so may result in regulatory action without further notice such as seizure and/or injunction.

You should notify this office in writing of the steps you have taken to bring your firm into compliance with the law within fifteen (15) working days of receiving this letter. Your response should include each step that has been taken or will be taken to correct the violations and prevent their recurrence. If corrective action cannot be completed within fifteen (15) working days of receiving this letter, state the reason for the delay and the time frame within which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made.

Your written response should be sent to Stephen J. Rabe, Compliance Officer, U.S. Food and Drug Administration, 6751 Steger Drive, Cincinnati, Ohio 45237. If you have any questions about this letter, please contact Mr. Rabe at 513-679-2700 ext. 163.

Sincerely, /S/

Karen Gale Sego Acting District Director Cincinnati District

Cc: Dr. William Thorn University of Kentucky Division of Regulatory Service 103 Regulatory Service Building Lexington, KY 40546-0275

Recent research has demonstrated that many swine and swine farmers in the Netherlands and Canada are colonized with MRSA. However, no studies to date have investigated carriage of MRSA among swine and swine farmers in the United States (U.S.).

We sampled the nares of 299 swine and 20 workers from two different production systems in Iowa and Illinois, comprising approximately 87,000 live animals. MRSA isolates were typed by pulsed field gel electrophoresis (PFGE) using SmaI and EagI restriction enzymes, and by multi locus sequence typing (MLST). PCR was used to determine SCCmec type and presence of the pvl gene.

In this pilot study, overall MRSA prevalence in swine was 49% (147/299) and 45% (9/20) in workers. The prevalence of MRSA carriage among production system A's swine varied by age, ranging from 36% (11/30) in adult swine to 100% (60/60) of animals aged 9 and 12 weeks. The prevalence among production system A's workers was 64% (9/14). MRSA was not isolated from production system B's swine or workers. Isolates examined were not typeable by PFGE when SmaI was used, but digestion with EagI revealed that the isolates were clonal and were not related to common human types in Iowa (USA100, USA300, and USA400). MLST documented that the isolates were ST398.

These results show that colonization of swine by MRSA was very common on one swine production system in the midwestern U.S., suggesting that agricultural animals could become an important reservoir for this bacterium. MRSA strain ST398 was the only strain documented on this farm. Further studies are examining carriage rates on additional farms.

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Discussion

This study is the first to document MRSA in U.S. swine and swine workers, and to our knowledge, the first to report the presence of ST398 (also reported as non-typeable MRSA, NT-MRSA) [15] in the U.S. Like previous studies in Canada, Denmark, and the Netherlands [11], [12], [24], ST398 was found in both animals and humans, suggesting transmission between the two. The prevalence of MRSA colonization among swine and swine workers was high at one farm system that we examined in the Midwestern U.S., suggesting that agricultural animals could become an important reservoir for this bacterium. Strain ST398 was the only MRSA identified among the swine and swine workers. This strain has been the predominant strain among swine in the Netherlands and Canada. However, Khanna et al. in Canada recently found both ST398 and ST5/USA100 colonizing the nares of swine and swine workers [12]. This difference may indicate that the epidemiology of MRSA on Canadian swine farms is different than on the affected farm system in Iowa and Illinois. On the other hand, the difference may have resulted from differing sampling methodologies. Khanna et al. sampled a small number of humans and swine on 20 farms whereas we took a larger number of samples from a smaller number of farms in two corporate systems. Furthermore, because we did not type all isolates in this pilot study, additional strain types may be present that we did not detect.

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In summary, we report the first isolation of MRSA from swine and swine workers in the U.S. Although the extent of this problem in the U.S. is currently unknown, our findings may have important implications for the epidemiology of MRSA disease. For example, Van Loo et al. identified MRSA in meat products in the Netherlands [32], suggesting that persons who handle raw pork products might be at risk for acquiring MRSA. Future studies should assess the risk of MRSA disease among swine workers and their contacts, survey retail meat products for MRSA contamination, study larger populations of swine and humans to define the epidemiology of MRSA within swine operations, and assess MRSA carriage rates in other livestock.

Abstract Closely related Staphylococcus aureus strains of ST398, an animal-associated strain, were identified in samples collected from humans in northern Manhattan, New York, NY, USA, and in the Dominican Republic. A large population in northern Manhattan has close ties to the Dominican Republic, suggesting international transmission.

Introduction

In the past 5 years, as methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a community pathogen, awareness of the role of animal exposure from pets or farming as sources of MRSA has increased.[1-3] We identified a clone of S. aureus previously associated with outbreaks of infections in animals and in humans who work with animals in 2 unique collections of S. aureus isolates. The first was from a population-based study of S. aureus colonization among residents of northern Manhattan in New York, NY, USA; the second was from isolates obtained from the Dominican Republic. This clone does not digest with the restriction enzyme SmaI, which is generally used for pulsed-field gel electrophoresis (PFGE). Consequently, the clone is identified by multilocus sequence typing as sequence type 398 (ST398). Both methicillin-resistant and methicillin-susceptible isolates of S. aureus have been reported.[4] ST398 has been found primarily in Europe, where it has been isolated from pigs and pig farmers in the Netherlands and France and from dogs, pigs, horses, and humans in Germany and Austria.[5-8] Colonization with MRSA ST398 has recently been reported in pigs and pig farmers in Canada.[9]

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The Study

The community-based study was conducted from 2004 through 2007 in the northern section of Manhattan, a borough of New York City. Northern Manhattan contains a large, medically underserved population that has close ties to the Dominican Republic. Participants were recruited by using random-digit dialing. Consenting persons and household members were subsequently interviewed and screened for S. aureus colonization. A total of 321 eligible households containing 914 household members participated. In 9 households, 13 participants were found to be colonized with S. aureus isolates that were SmaI resistant. Digestion with the Cfr9I, an isoschizomer of SmaI, yielded identical PFGE profiles (Figure). Subsequent multilocus sequence typing confirmed the ST398 identification (allelic profile 3-35-19-2-20-26-39). All strains were methicillin susceptible. A representative strain was spa-typed as type t571 (allelic profile 8-16-2-25-2-25-34-25, eGenomics type 109); it was Panton-Valentine leukocidin negative.

Characteristics of persons colonized with ST398 were similar to those of persons in the community-based study and with northern Manhattan census characteristics (Table). The 13 isolates were from 9 different families; 1 family had 4 members colonized with ST398 at either nasal or axillary sites. The mean age of those colonized was 33.4 years; only 1 child (7 years of age) was colonized. Two persons from different families were colonized with ST398 at multiple sites, none of which were confirmed as infections.

No household reported owning pets, although 2 reported animal contact. Of the 12 adults, 5 (41.7%) reported possible job exposure to S. aureus, including 1 who worked in a healthcare-associated field. No household reported patronizing viveros, or live poultry markets, which are common in the Latino communities of northern Manhattan and the Bronx. Two households reported having children who attended day care, although none of these children were colonized with S. aureus. Although 15% of the Dominican population in the study reported travel to the

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Dominican Republic within 6 months of their interview, none of the colonized participants reported recent travel to the Dominican Republic. No contact among the different households was reported.

Received 11 July 2007/ Returned for modification 11 September 2007/ Accepted 13 November 2007

ABSTRACT

Five of the seven cases of vancomycin-resistant Staphylococcus aureus (VRSA) infection identified to date have occurred in southeastern Michigan. VRSA isolates from the four most recent cases (all from Michigan) were characterized. The vanA gene was localized to a single plasmid in each VRSA isolate. The pulsed-field gel electrophoresis patterns of chromosomal DNA and the restriction profile of the plasmid demonstrated that the four isolates were unique and differed from the first three VRSA isolates. Vancomycin-resistant Enterococcus (VRE) isolates, all of which were Enterococcus faecalis, were recovered from case patients 4 to 6. Each VRE isolate transferred vancomycin resistance to E. faecalis JH2-2 by conjugation. PCRs for vanA and the Inc18-like plasmid genes traA and repR confirmed the presence of an Inc18-like vanA plasmid in all VRE isolates and transconjugants. An Inc18-like vanA plasmid was identified in the VRSA isolate from case patient 7. These findings suggest a role of Inc18-like plasmids as vanA donors.

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The occurrence of VRSA appears to be either a one- or a two-step genetic event. The plasmid from the first VRSA isolate was sequenced and was found to be a previously recognized S. aureus plasmid containing a Tn1546 insertion (35). The proposed model of resistance transfer was a two-step genetic event in which the S. aureus isolate acquired the Enterococcus vanA plasmid, Tn1546 transferred from the Enterococcus plasmid to the S. aureus plasmid by transposition, and the Enterococcus plasmid was not maintained in the S. aureus recipient. In the third VRSA case, the entire Enterococcus vanA plasmid was maintained in the S. aureus recipient (36). This suggests a single genetic event in which the vanA plasmid is transferred from one isolate to the next, most likely by conjugation. In our analysis of the Michigan VRSA isolates, both outcomes were observed.

It is not clear how common VRSA will be in the future, but this is certainly a concerning antimicrobial resistance that should be prevented, if possible. An important aspect of VRSA prevention will be the control of VRE and methicillin-resistant S. aureus transmission. This is a challenging prospect, since both VRE and methicillin-resistant S. aureus are endemic in most health care settings in the United States (4). It may be prudent to implement the most rigorous control measures for patient populations and at locations where VRE isolates with Inc18-like plasmids occur.

Methicillin-resistant Staphylococcus aureus (MRSA) is well-recognised as a major cause of infection in the healthcare setting but, even more worryingly, is now emerging in the community. The glycopeptides-notably vancomycin-have traditionally been the mainstay of treatment of MRSA but overuse has led to the emergence of vancomycin-intermediate and vancomycin-resistant MRSA (VISA and VRSA, respectively). Although the mechanisms underlying vancomycin resistance are not yet fully understood, changes to the bacterial cell wall-the site of action of the glycopeptides-are believed to be key. Recent evidence also supports the transfer of genetic material among bacteria as contributing to the development of VRSA. Based on the cases identified to date, risk factors for the development of VRSA may include older age, compromised blood flow to the lower limbs, and the presence of chronic ulcers. The true extent of the problem, however, remains to be determined-it is likely that many cases of VISA and VRSA infection go undetected because of suboptimal screening programmes and possible limitations of automated and non-automated detection methods. Effective screening directed at those patients considered to be most at risk should therefore be a priority. Not surprisingly, the spread of MRSA from the hospital to the community setting, coupled with the emergence of VISA and VRSA, has become a major cause of concern among clinicians and microbiologists. The treatment options available for these infections are now severely compromised and thus new classes of antimicrobial agents effective against MRSA, VISA and VRSA are urgently required.

Rates of colonization with livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) sequence type 398 have been high for pigs and pig farmers in Canada, but prevalence rates for the general human population are unknown. In this study, 5 LA-MRSA isolates, 4 of which were obtained from skin and soft tissue infections, were identified from 3,687 tested MRSA isolates from persons in Manitoba and Saskatchewan, Canada. Further molecular characterization determined that these isolates all contained staphylococcal cassette chromosome (SCC) mecV, were negative for Panton-Valentine leukocidin, and were closely related by macrorestriction analysis with the restriction enzyme Cfr91. The complete DNA sequence of the SCCmec region from the isolate showed a novel subtype of SCCmecV harboring clustered regularly interspaced short palindromic repeats and associated genes. Although prevalence of livestock-associated MRSA seems to be low for the general population in Canada, recent emergence of infections resulting from this strain is of public health concern.

High prevalence of colonization with livestock-associated (LA) methicillin-resistant Staphylococcus aureus (MRSA) sequence type (ST) 398 among pigs and pig farmers was first

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reported in the Netherlands (1) and has since been identified in Canada (2) and the United States (3). In Canada, this LA-MRSA strain was identified in pigs and pig farmers in southwestern Ontario, where prevalence of MRSA colonization was 24.9% (71/285) and 20% (5/25), respectively (2). In the United States, nasal samples from 20 production system workers and 299 swine from 2 farms in Illinois and Iowa showed that 45% (9/20) and 49% (147/299), respectively, were colonized with LA-MRSA (3). Despite such high prevalence of MRSA colonization on these tested farms, to our knowledge, no human or animal infections resulting from LA-MRSA strains have been reported in North America. To determine whether LA-MRSA has recently emerged in the general population of Canada, we identified human infections and colonizations associated with the LA-MRSA strain in Canada and molecularly characterized the isolates. We also identified a novel staphylococcal cassette chromosome (SCC) mecV subtype harboring clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (cas).

SNIP...

Discussion

The high prevalence of LA-MRSA colonization of pigs and pig farmers in Canada (2) and the United States (3) and this report of human infections suggest that this LA-MRSA strain from Canada poses potential public and occupational health concern in North America. This strain has been associated with various types of infections in pigs (17,18) and humans (19,20) and is transmissible from animal patients to veterinary workers (21), healthcare workers (22), and family members (1). Evidence also suggests that this strain might be spreading from animals to the environment, which may facilitate the colonization or infection of persons who are not involved in animal husbandry (23). Whereas in 2006 in the Netherlands LA-MRSA accounted for >20% of all MRSA isolated (24), carriage of this strain in the general population of 2 provinces in Canada (Manitoba and Saskatchewan) appears rare (0.14%). This difference could be attributed to the substantially higher density of pigs in the Netherlands (1,244 pigs/km2) than in Manitoba (55 pigs/km2), Saskatchewan (6 pigs/km2), and Ontario (91 pigs/km2) (www.agriculture.gov.sk.ca/Pig_Densities). It is also plausible that the much lower proportions of LA-MRSA in Canada, relative to a country with low MRSA endemicity such as the Netherlands, is attributable to competition with other highly successful human epidemic MRSA clones circulating in Canada, including CMRSA2 (USA200/800), CMRSA7 (USA400), and CMRSA10 (USA300) (25,26). The tested LA-MRSA isolates were highly susceptible to most classes of antimicrobial drugs, except ß-lactams and tetracyclines, the latter of which has been attributed to its high usage in animal husbandry (27). The complete sequence of the SCCmec region showed a novel SCCmecV subtype sharing sequence identity in its J1 and J3 regions with chromosomal genes in the S. epidermidis RP62A chromosome (GenBank accession no. CP000029), including a

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CRISPR system. CRISPRs and associated cas genes are present in many other bacterial (˜40%) and archaeal (˜90%) genomes (28,29) and have been shown to be involved in sequence-directed immunity against phages (30,31) and plasmids (32). The resistance to plasmids and phages encoded by this system could explain why many of these ST398-MRSA-V strains contain fewer antimicrobial drug resistance genes and phage-encoded virulence factors than do other epidemic MRSA strains (33,34). The origin of this CRISPR system is unknown, but the propagation of CRISPR loci throughout prokaryote genomes has been proposed to occur through horizontal gene transfer by conjugation of megaplasmids >40 kb (35). Because the CRISPR system identified in this study is encoded within a putative mobile genetic element, we propose that an additional mechanism of mobilization to other methicillin-susceptible Staphylococcus spp. is plausible.

This novel subtype of SCCmecV was found in only 4 of the 6 LA-MRSA isolates identified in this study. One isolate not containing this novel SCCmec subtype (08 BA 08100) could also be distinguished by a different but closely related spa type (t1250) (Table 1) and variant PFGE fingerprint (Figure 2) when compared with the other LA-MRSA isolates, which suggests that at least 2 epidemiologically different strains of LA-MRSA circulate in Saskatchewan. The other LA-MRSA isolate that did not contain this novel SCCmec element was obtained in Ontario. However, this isolate was the same spa type (t034) and was closely related, according to PFGE, to the LA-MRSA isolates identified in Saskatchewan. Therefore, in addition to PFGE and spa typing, SCCmec subtyping could provide a useful epidemiologic tool for surveillance, outbreak investigations, or traceability studies of this emerging strain. For detection of this SCCmecV subtype (tentatively designated V.2.1.2; Vb), we propose using primer set 1 (spanning orfX into Sk02 in the J3 region) and primer set 7 (spanning Sk20 into cas1 in the J1 region) (Table 4).

Visual comparison of PFGE fingerprints from this study with those reported from patients from the Dominican Republic and the United States (northern Manhattan, New York, NY) (36), showed substantial variations in fingerprint patterns, as well as related but different spa types. These variations suggest further molecular and geographic diversity of these LA-MRSA strains on a global scale.

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Because cases of LA-MRSA infections have only recently been identified in Canada, additional surveillance efforts are required to monitor the emergence and clinical relevance of this MRSA strain in Canada, including communities, the environment, livestock, farmers, and production facility workers. Whether these strains pose a major threat to human health in light of the low livestock density and continued spread of epidemic hospital and community strains of MRSA in Canada remains unknown.

Abstract During 2001–2002, high-level gentamicin-resistant (HLGR) Enterococcus faecalis isolates were detected in 2 patients in Denmark who had infective endocarditis and in pigs and pork. Our results demonstrate that these isolates belong to the same clonal group, which suggests that pigs are a source of HLGR E. faecalis infection in humans.

snip...

Conclusions Our study provides evidence of the existence of a widespread community reservoir of HLGR ST16 in pigs in Denmark during 2001–2002, which coincided with emergence of HLGR ST16 isolates among IE patients in North Denmark Region. One isolate was present in pork, which supports foodborne transmission, although direct transmission from animals to humans is also possible.

Our study has potential limitations. First, the method used by DANMAP (susceptibility testing of 1 colony per sample, rather than resistance prevalence per sample) may underestimate the extent of the HLGR reservoir in food-producing animals, meat products, and community-dwelling persons. Second, HLGR isolates from patients with infective endocarditis emanated from 2001 and 2002 and therefore do not represent recent trends.

Our findings support the results of a recent study in the United States that identified HLGR E. faecalis isolates with similar PFGE patterns (<3-band>22 million slaughter pigs (4–6), Denmark has a large potential reservoir of HLGR ST16. Although HLGR ST16 was not detected in other food-producing animals and meat products, this type may not be exclusive to pigs. We found HLGR ST16 isolates in 2 community-dwelling persons during 2003–2005. Preference for eating pork, close contact with the healthcare setting, underlying disease, or a combination thereof may have predisposed these persons to become colonized by this potential pathogen.

HLGR ST16 appears to be transmitted from pigs to humans, although other routes of transmission also may exist. Further studies are needed to better understand the human and veterinary epidemiology of this zoonosis. Areas of study should include recent trends of HLGR among invasive E. faecalis; size of the reservoir in pigs; its association with antimicrobial drug use in pigs; and whether other animals, immunocompromised persons, or healthy persons constitute a community reservoir of HLGR ST16.

On January 14, and 20, 2010, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 280 West 110 South, Murtaugh, Idaho. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on the FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii), a food is deemed to, be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. § 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about September 17, 2009, you sold a dairy cow, identified with Back Tag number (b)(4), for slaughter as food to (b)(4) where it was subsequently slaughtered on that same day. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from that animal identified the presence of Flunixin at 1.494 parts per million (ppm) in the liver. FDA has established a tolerance of 0.125 ppm for residues of Flunixin in the edible tissues of cattle, as codified in Title 21, Code of Federal Regulations, Section 556.286 (21 C.F.R. 556.286).

The presence of Flunixin in edible tissues from this animal in this amount causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. You lack an adequate system to ensure that animals medicated by you have been withheld from slaughter for appropriate periods of time to permit depletion of potentially hazardous residues of drugs from edible tissues.

For example, you failed to maintain records regarding the identity of animal(s) that you delivered for sale to (b)(4). Specifically, your treatment records are correlated to the numbered ear tags that you apply to the individual cows. On or about September 17, 2009, you sold seven cows for slaughter and removed the ear tags prior to them leaving your premises. You failed to correlate the ear tag numbers with back tag numbers, (b)(4) applied by (b)(4) when they picked up the cows and thereby lost the true identity of the cows and the ability to provide treatment records for those individual cows.

Additionally, you failed to have a system to control the administration of drug treatments to your animals. Specifically, it appears that the cow identified by back tag number (b)(4) was administered Banamine (Flunixin meglumine) and the treatment was never recorded. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4).

An inspection of your operation located in Middlebury, VT, by a Food and Drug Administration investigator on September 22, 2009, September 24, 2009, October 7, 2009 and November 4, 2009, confirmed a dairy cow identified with back tag (b)(4), ear tag # (b)(4), and farm tag (b)(4) purchased and sold by you on or about April 7, 2009, for slaughter for human food to (b)(4), was in violation of Section 402 (a)(2)(C)(ii) of the Federal Food, Drug, and Cosmetic Act (the Act). USDA/FSIS analyses of tissues collected from that animal disclosed the presence of the following drugs:

* Tolerances have been established for residues in the edible tissues of dairy cows which are codified in Title 21 Code of Federal Regulations Section 556.

In addition, USDA has reported the finding of illegal residues in other livestock sold by you and offered for slaughter for human drugs. Copies of letters from USDA/FSIS notifying you of these residues are attached.

* Tolerances have been established for residues in the edible tissues of dairy cows which are codified in Title 21 Code of Federal Regulations

In addition, your firm has employed poor husbandry practices by failing to take reasonable precautions to prevent the marketing and sale of animals containing illegal residues in interstate commerce. Your significant violations are as follows:

1. You have failed to implement and maintain a system to identify the animals you purchase with records to establish traceability to the source of the animal. Specifically on or about April 7, 2009 you purchased and sold a cow in interstate commerce, identified with back tag # (b)(4), ear tag # (b)(4), and farm tag # (b)(4), however you maintained no documentation as to the origin of the cow.

2. You have failed to determine from the source of the animal whether the animal has been medicated and with what drug(s). Specifically, since 2000 you have purchased and sold at least (b)(4) livestock animals for slaughter that have been found to contain violative tissue residues. You answered in the negative when asked if you inquire about the medication status of the animal from the source.

Pursuant to section 301(a) {U.S.C. § 331(a)} of the Act the introduction or delivery for introduction into interstate commerce of any food that is adulterated is prohibited.

On November 3 and 5, 2009, the U.S. Food and Drug Administration (FDA) conducted an investigation of your calf raising operation located at 756 South 2800 East, Hazelton, Idaho 83335-5280. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the. Internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale animals for slaughter as food that were adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about August 14, 2009, you sold a calf, identified with back tag (b)(4), for slaughter as food. On or about August 14, 2009, (b)(4) slaughtered this animal. In addition, our investigation revealed that on or about August 26, 2009, you sold a calf, identified with back tag (b)(4) for slaughter as food. On or about August 26, 2009, this animal was also slaughtered at (b)(4). United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from these animals identified the presence of gentamicin sulfate in the kidney tissues. FDA has not established a tolerance for residues of gentamicin sulfate in the edible tissues of cattle. The presence of this drug in edible tissue from these animals causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain treatment records for the animals identified with back tags (b)(4) and (b)(4) Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4).

We also found that you adulterated the new animal drug gentamicin sulfate. Specifically, our investigation revealed that you did not use gentamicin sulfate as directed by the veterinarian's prescription labeling nor as directed by its approved labeling. Use of this drug in this manner is an extralabel use. See Title 21, Code of Federal Regulations, Section 530.3(a) (21 C.F.R. 530.3(a)).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Our investigation found that you administered gentamicin sulfate to two calves, back tags (b)(4) and (b)(4) without following the dose and withdrawal period as stated in the veterinarian's prescription labeling nor as directed by its approved labeling. Your extralabel use of gentamicin sulfate resulted in an illegal drug residue, in violation of 21 C.F.R. 530.11 (c). Because your use of this drug was not in conformance with its approved labeling and did not comply with 21 C.F.R. Part 530, you caused the drug to be unsafe under section 512(a) of the Act, 21 U.S.C. 360b(a), and adulterated within the meaning of section 501(a)(5) of the Act, 21 U.S.C. 351(a)(5).

On June 30 and July 2, 2009, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 1587 East 3100 South, Wendell, Idaho. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on the FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii) a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about February 17, 2009, you sold 12 cows for slaughter to (b)(4) one of which was identified by (b)(4) with back tag (b)(4) On or about February 18, 2009 (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of 3.55 parts per million (ppm) of penicillin residue in the liver, 10.62 ppm in the muscle, and 2.29 ppm in the kidney tissue. FDA has established a tolerance for residues of penicillin in the uncooked edible tissues of cattle at 0.05 ppm as codified in Title 21, Code of Federal Regulations, Section 556.510(a) (21 C.F.R. 556.510(a)). The presence of this drug in edible tissue from this animal in this amount causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain complete treatment records. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4).

We also found that you adulterated the new animal drug Penicillin G Procaine Injectable Solution. Specifically, our investigation revealed that you did not use this drug as directed by its approved labeling. Use of this drug in this manner is an extralabel use. 21 C.F.R. 530.3(a).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/c1ienUpatient relationship.

Our investigation found that in February 2009 you administered Penicillin G Procaine to the cow identified by back tag (b)(4) without following the indications or dosing instructions as stated in the drug's approved labeling. Your extralabel use of Penicillin G Procaine was not under the supervision of a licensed veterinarian, in violation of 21 C.F.R. 530.11 (a). Furthermore, your extralabel. use of Penicillin G Procaine in the cow identified by back tag (b)(4) resulted in an illegal drug residue, in violation of 21 C.F.R. 530.11 (d). Because your extralabel uses of this drug were not in conformance with its approved labeling and did not comply with 21 C.F.R. Part 530, you caused the drug to be unsafe under section 512(a) of the Act, 21 U.S.C. 360b(a), and adulterated within the meaning of section 501 (a)(5) of the Act, 21 U.S.C. 351 (a)(5).

On May 7, 2009, and June 3, 2009, the U.S Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 10720 Township Road 526, Shreve, Ohio. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 360b.

Specifically, our investigation revealed that on or about October 15, 2008, you sold a Holstein bull veal calf for slaughter as food through (b)(4), where the Holstein bull veal calf was identified with back tag # (b)(4). On or about October 16, 2008, (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected on October 16,2008 from this bull veal calf with back tag (b)(4) identified the presence of 0.66 parts per million (ppm) sulfamethoxazole in the liver and 0.70 ppm sulfamethoxazole in the muscle of this animal. The FDA has not established a tolerance for residue associated with use of sulfamethoxazole in the edible tissue of veal calves as codified in Title 21, Code of Federal Regulations (C.F.R.), Part 556 (21 C.F.R. Part 556). The presence of this drug in the edible tissue of this bull veal calf in these amounts causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii).

We also found that you violated section 501(a)(5) of the Act, 21 U.S.C. 351(a)(5), when your employees administered Sulfamethoxazole and Trimethoprim Tablets, 800 milligrams (mg)/160 mg, Double Strength (NDC 61971-120-05) to the bull veal calf. Specifically, our investigation revealed that sulfamethoxazole and trimethoprim tablets were used in an extralabel manner by a layperson on your farm outside the orders, instructions, or supervision of a licensed veterinarian in violation of 21 C.F.R. 530.1 I (a), and the use of these tablets resulted in sulfamethoxazole residue which may present a risk to public health, in violation of 21 C.F.R. 530.11(c).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512 (a)(4) and (5) of the Act, 21 U.S.C. 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Because the use of the sulfamethoxazole and trimethoprim tablets did not comply with 21 C.F.R. Part 530, you caused the drug to be unsafe under section 512(a) of the Act, 21 U.S.C. 360b(a), and thus adulterated within the meaning of section 501 (a)(5) of the Act, 21 U.S.C. 351(a)(5).

On April 2 and 9, 2009, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy farm located at 403 State Highway 72, Potsdam, New York 13676. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about October 15, 2008, you sold a dairy cow, identified with farm tag#(b)(4) for slaughter. On or about October 16, 2008, (b)(4) slaughtered this animal. The United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of 0.82 parts per million (ppm) of penicillin residue in the kidney tissue. FDA has established a tolerance for residues of penicillin in the uncooked edible tissues of cattle at 0.05 ppm as codified in Title 21, Code of Federal Regulations, Section 556.510(a) [21 C.F.R. 556.510(a)]. The presence of this drug in edible tissue from this animal causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain accurate treatment records and you lack an adequate system to ensure that animals medicated by you have been withheld from slaughter for appropriate periods of time to permit depletion of potentially hazardous residues of drugs from edible tissues. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. 342(a)(4).

We also found that you adulterated the new animal drugs (b)(4) (Penicillin G Procaine Injectable Suspension), (b)(4) (ceftiofur hydrochloride), and (b)(4) (hetacillin potassium). Specifically, our investigation revealed that you did not use (b)(4) and (b)(4) as directed by their approved labeling. Use of these drugs in this manner is an extralabel use. See 21 C.F.R. 530.3(a).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Our investigation found that you administered the drugs (b)(4) and (b)(4) without following the dosage levels as stated in the approved labeling. Your extralabel use of these drugs was not under the supervision of a licensed veterinarian, in violation of 21 C.F.R. 530.11(a). Furthermore, your extralabel use of (b)(4) resulted in an illegal residue, in violation of 21 C.F.R. 530.11(d). In addition, you administered the drug (b)(4) without following the withdrawl period for slaughter set forth in the approved labeling. Specifically, you administered the drug (b)(4) on October 9, 2008, and then sold the dairy cow identified with farm tag # (b)(4) for slaughter on October 15, 2008. The approved labeling of (b)(4) states treated animals must not be slaughtered for food until ten days after the latest treatment. Because your extralabel use of these drugs was not in compliance with 21 C.F.R. Part 530, these drugs were unsafe under section 512(a) of the Act, 21 U.S.C. 360b(a), and your use caused them to be adulterated within the meaning of section 501(a)(5) of the Act, 21 U.S.C. 351(a)(5).

On April 24 and 30, 2009, the U.S. Food and Drug Administration (FDA) conducted an inspection of your dairy operation located at 3209 S 1800 E, Wendell, Idaho. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on the FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. § 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our inspection revealed that on or about December 1, 2008, you sold a dairy cow, identified with back tag (b)(4) for slaughter as food. On or about December 1, 2008, (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of flunixin at 2.5735 parts per million (ppm) in the liver. FDA has established a tolerance of 125 parts per billion (0.125 ppm) for residues of flunixin in the liver tissues of cattle, as codified in Title 21, Code of Federal Regulations, Section 556.286 (21 C.F.R. 556.286). The presence of flunixin in the liver tissues from this animal in this amount causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain complete treatment records. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4).

We also found that you adulterated the new animal drug flunixin. Specifically, our investigation revealed that you did not use flunixin as directed by its approved labeling. Use of this drug in this manner is an extralabel use, 21 C.F.R. 530.3(a).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. § 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Our investigation found that you routinely administer flunixin to your animals without following the route of administration or withhold time as stated in the approved labeling. Your extralabel use of flunixin is not under the supervision of a licensed veterinarian, in violation of 21 C.F.R. 530.11 (a). Because your use of this drug is not in conformance with its approved labeling and does not comply with 21 C.F.R. Part 530, you cause the drug to be unsafe under section 512(a) of the Act, 21 U.S.C. § 360b(a), and adulterated within the meaning of section 501 (a)(5) of the Act, 21 U.S.C. § 351 (a)(5).

On December 12 and 18, 2008, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 3167 Kissel Hill Road, Lititz, Pennsylvania. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during Our investigation of your operation: You can find the Act and its associated regulations on the Internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act 21 U.S.C. § 342 (a)(2)(C)(ii) a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. 21 U.S.C. § 360b. Further, Under section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about July 7, 2008, you sold a dairy cow, identified with back tag (b)(4), and ear tag (b)(4) for slaughter as food. On or about July 8, 2008, (b)(4) located in (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of sulfadimethoxine in the liver at 0.95 parts per million (ppm) and in the muscle at 1.03 ppm and penicillin in the liver at 0.13 ppm FDA has established a tolerance for residues of sulfadimethoxine in the uncooked edible tissues of cattle at 0.1 ppm as codified in Title 21, Code of Federal Regulations, Section 556.640 (21 C.F.R. 556.640,and a tolerance for residues of penicillin in the uncooked edible tissues of cattle at 0.05 ppm as codified in 21 C.F.R. 556.510 The presence of these drugs in edible tissue from this animal in these amounts causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. You lack an adequate system to ensure that animals medicated by you have been withheld from slaughter for appropriate periods of time to permit depletion of potentially hazardous residues of drugs from edible tissues. For example, you failed to maintain treatment records. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4).

We also found that you adulterated the new animal drugs sulfadimethoxine and penicillin. Specifically, our investigation revealed that you did not use sulfadimethoxine and penicillin as directed by their approved labeling. Use of these drugs in this manner is an extralabel use. 21 C.F.R. 530.3(a).

The extralabel use of approved animal or human drugs in animals is allowed under the Act only if the extralabel use complies with sections 512(a)(4) and (5) of the Act, 21 U.S.C. §§ 360b(a)(4) and (5), and 21 C.F.R. Part 530, including that the use must be by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship.

Our investigation found that you administered sulfadimethoxine to a dairy cow identified with back tag (b)(4) and eartag (b)(4), without following the indications for use contained in the approved labeling. Sulfadimethoxine is prohibited for extralabel use in lactating dairy cows by 21 C.F.R. 530.41(a)(9). Further, your extralabel use of this drug resulted in illegal drug residues in this animal, in violation of 21 C.F.R. 530.11(d). In addition, our investigation found that you administered penicillin to a dairy cow, identified with back tag (b)(4) and ear tag (b)(4) without following the indications for use or dose contained in the approved labeling. Your extralabel use of penicillin was not under the supervision of a licensed veterinarian, in violation of 21 C.F.R. 530.11(a) and your extralabel use resulted in an illegal drug residue, in violation of 21 C.F.R. 530.11(d). Because your extralabel uses of these drugs was not in conformance with their approved labeling and did not comply with 21 C.F.R. Part 530, you caused the drugs to be unsafe under section 512(a) of the Act, 21 U.S.C. § 360b(a), and adulterated within the meaning of section 501(a)(5) of the Act, 21 U.S.C. § 351(a)(5).

On April 23, 24, and 27, May 7 and 19, and June 18,2009, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at 12471 Thomas Road, South Charleston, Ohio 45368. This letter notifies you of the violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on FDA's web page at www.fda.gov.

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii), a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act, 21 U.S.C. § 360b. Further, under section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4), a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.

Specifically, our investigation revealed that on or about June 30, 2008, you sold ten calves, one of which was a bull calf that was given back tag (b)(4) by the hauler and sold for slaughter as food. On or about July 1, 2008, (b)(4) of (b)(4) slaughtered this animal. The United States Department of Agriculture, Food Safety and Inspection Service (USDAJFSIS) analysis of tissue samples collected from this animal identified the presence of 10.95 ppm neomycin in the kidney. FDA has established a tolerance of 7.2 ppm of neomycin in the kidney of cattle as codified in Title 21, Code of Federal Regulations, Section 556.430 (21 C.F.R. 556.430). The presence of this drug in the edible tissue from this animal in this amount causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act, 21 U.S.C. § 342(a)(2)(C)(ii).

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain complete treatment records and failed to identify treated animals. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act, 21 U.S.C. § 342(a)(4).